This invention relates to novel benzimidazole derivatives, and more specifically, 3-(2-(2-phenylethyl)benzimidazol-4-yl)-3-hydroxypropanoic acid and its esters, and compounds and optically active compounds thereof; a process for producing the same; drugs containing at least one of these compounds as the active ingredient, and in particular, a drug for preventing and/or treating diseases exhibiting eosinophilia, bronchial asthma or allergic diseases; otherwise an enhancer for interferon-y production, and in particular, an antitumor agent or an antiviral agent based on the action of enhancing the production of the interferon-xcex3 which is effective in oral administration.
A phenomenon in which eosinophils increase in blood or tissues, namely differentiating, Inducing or infiltrating phenomenon, is observed in many diseases. It is important from the clinical point of view to differentiate these diseases between certain diseases in which eosinophilia is frequently observed but its direct concern in pathophysiology is no and other diseases in which eosinophils are probably concerned as the main immune cell in the pathophysiology of such diseases. Addison disease, ulcerative colitis and the like diseases can be exemplified as diseases which correspond to the former case. Examples of the latter case include parasite infection, hypereosinophilic syndrome (HES), eosinophilic pneumonia, eosinophilic enterogastritis, bronchial asthma and the like diseases. Since eosinophils are closely related to the pathophysiology of bronchial asthma, so-called eosinophilic bronchitis is recently taking root as a pathophysiology concept. Particularly, there are some common points among movements of eosinophils which are concerned in these diseases. That is, they are summarized into three points of 1) acceleration of eosinophil production and differentiation by eosinophil growth lymphokines mainly including interleukin 5 (IL-5), 2) migration and accumulation of eosinophils into an involved organ by eosinophil chemotactic activity and 3) activation of eosinophils and prolongation of their life survival in the morbid sites. It is considered that the just described three factors or matters exert tissue damage and inflammation inducing actions of eosinophils in these diseases, thereby concerning in their pathophysiology, though there are differences in terms of foci and the degree of clinical symptoms. Also, though there are differences in terms of the increasing degree of eosinophils, atopic dermatitis, allergic rhinitis and the like various diseases can be exemplified as the diseases which exhibit eosinophilia (S. Nakajima and J. Shigehara, Meaning of the Clinical Diagnoses of eosinophils, xe2x80x9cEosinophilsxe2x80x9d ed. by S. Makino and K. Ishikawa, pp. 165-173, Kokusai Igaku Shuppan, 1991).
In consequence, a compound which controls eosinophils, or inhibits increment or activation of eosinophils in blood or tissues, could be applied to parasite infection, hypereosinophilic syndrome (HES), eosinophilic pneumonia, eosinophilic enterogastritis, bronchial asthma, atopic dermatitis, allergic rhinitis and the like diseases that exhibit eosinophilia.
Under the present situation, only the administration of steroid drugs is attempted as a symptomatic therapy for the treatment of diseases which exhibit eosinophilia, and there are no therapeutic methods which target eosinophils. It is extremely difficult to use steroid drugs, because they frequently cause peculiar side effects such as reduction of resistance against bacterial infection, hyperglycemia, diabetes, gastric ulcer, hyperkalemia, osteoporosis, obesity and the like, and their use is strictly stipulated such as prohibition of sudden termination of their administration. In addition, conventional asthma-treating drugs have been developed mainly based on histamine release inhibition action and the like, and it has been revealed that eosinophils are closely concerned also in this pathophysiology, so that the use of eosinophils as a target could be applied to certain types of asthma which cannot be treated by the conventional method. Under such situation, a compound which has high safety and can strongly control eosinophils seems to be markedly useful in a method of fundamental medical treatment of various diseases in which eosinophilia is concerned, so that realization of such a compound as a pharmaceutical preparation is strongly desired.
With regard to a compound of benzimidazole skeleton having a phenylethyl side chain on its partial structure, JP-A-3-109378 discloses that certain compounds having actions to inhibit both cyclooxygenase (CO) and lipoxygenase (LO) enzymes are useful in treating or alleviating allergic or inflammatory conditions, but it does not disclose their pharmacological data so that the strength of action of each compound and its detailed action mechanism are not clear (the term xe2x80x9cJP-Axe2x80x9d as used herein means an xe2x80x9cunexamined published Japanese patent applicationxe2x80x9d). Also, JP-A-61-65848 discloses a compound which selectively inhibits 5-lipoxygenase and discloses that it is effective in a rat adjuvant arthritis model and inhibits release of SRS-A in rat passive peritoneal anaphylaxis (PPA). However, these prior art benzimidazole derivatives are different from the compounds of the present invention in terms of their structures, and these patents do not disclose about the effect of these derivatives to inhibit increment or activation of eosinophils.
With regard to a compound of benzimidazole skeleton having a carboxylic acid or ester structure on its side chain, U.S. Pat. No. 5,216,003 discloses a compound which is useful as an NMDA antagonist in neurodegenerative diseases and neurotoxin disorders. Structure of this prior art benzimidazole derivative is also different from that of the compound of the present invention, and the patent does not disclose actions against eosinophils.
With regard to the compounds which enhance the production of interferon-xcex3 (hereinafter abbreviated as IFN-xcex3), JP-A 10-251148 discloses that 1-(carbozole-4-iloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol and the optically active compounds thereof which are the promoters of the IFN-xcex3 production have the action of eliminating viral infection, and in particular, that such compounds are capable of reliably eliminating the cause of acute myocarditis associated with viral infection, and effectively treating the acute myocarditis. JP-A 8-143592 discloses that the peptides having the action of promoting the IFN-xcex3 production promote cell propagation in the cell culture of normal mouse hepatic cell line (NCTC Clone 1469) and such peptides specifically promote the IFN-xcex3 production of the cell in such cell culture. Furthermore, JP-A 4-208271 discloses that a promoter for the production of IFN-xcex3 and the compound having the action of promoting interleukine-2 (hereinafter abbreviated as to as IL-2) are capable of producing IFN-xcex3 and IL-2 from the monocyte of human peripheral blood, and such compounds are effective as a therapeutic agent for viral infection.
However, the compounds which promote the IFN-xcex3 production as described above are different in their structure from the compounds of the present invention. In addition, in spite of the disclosure of promoting the cytokine production by directly stimulating the immunocompetent cell, there is no indication of providing the immunocompetent cell with the character of increased basal production rate of IFN-xcex3 under stationary conditions without any immuno stimulation.
With regard to the benzimidazole derivatives, and in particular, 3-(2-(2-phenylethyl)benzimidazol-4-yl)-3-hydroxypropanoic acid and its esters, Kato et al. (The Journal of Immunology, vol.162, pages 7470-7479, 1999) reports that, when such compounds are orally administered and the splenocytes are cultured in the presence of an antigenic stimulant such as concanavalin A and ascarid extract, production of IL-4 and IL-5 is suppressed with simultaneous enhancement in the production of IFN-xcex3. However, there is no indication or teaching that such compound exhibits enhancement of the IFN-xcex3 production of immunocompetent cells when such compound is orally administered to a tumor-bearing mouse.
In developing pharmaceutical preparations, it is important in general that these medicaments show excellent results not only in pharmacological tests but also in safety tests such as a subacute toxicological test (for example, a two week drug tolerance test in rats), a chronic toxicological test, a reproductive/developmental toxicological test, a mutagenicity test, an experimental carcinogenicity test, a metabolism test and the like. It is very important to provide a drug having excellent pharmakokinetics such as absence of cytochrome P450-related drug metabolism in the liver, serological or pathological abnormality and the like, namely a drug which has high safety, is effective in a small amount and can be handled easily. However, no compound has been disclosed in the prior art that resolves such problems while inhibiting the increment or activation of eosinophils, or the compound that resolves such problems while exhibiting the enhancement of the IFN-xcex3 production.
In view of such situation, there is a strong desire of a drug which has oral bioavailability and high safety with no side effects and which can be handled with ease.
An object of the present invention is to provide compounds or a salt thereof which are effective against diseases exhibiting eosinophilia (parasite infection, hypereosinophilic syndrome (HES), eosinophilic pneumonia (PIE syndrome), eosinophilic enterogastritis, bronchial asthma, atopic dermatitis, allergic rhinitis and the like) or various allergic diseases (hay fever, pollinosis, allergic enterogastritis, food allergy, drug allergy and the like), through the regulation of eosinophils, namely inhibition of the increment or activation of eosinophils in blood or tissues, or through the inhibition of IgE antibody production; and compounds or a salt thereof which have the action of enhancing IFN-xcex3 production and which is useful as an antitumor agent. A further object of the present invention is to provide benzimidazole derivatives, and in particular 3-(2-(2-phenylethyl)benzimidazol-4-yl)-3-hydroxypropanoic acid and its esters, optically active compounds thereof, and a salt thereof.
A still further object of the present invention is to provide a process for producing the compounds as described above, and drugs and pharmaceutical compositions containing the such compound, and in particular, a prophylactic and/or therapeutic agent for diseases exhibiting eosinophilia, bronchial asthma and allergic diseases, in which at least one of the aforementioned problems involved in the prior art is resolved; or an enhancer for IFN-xcex3 production which exhibits oral bioavailability and excellent safety, and more specifically, an agent for enhancing IFN-xcex3 production, and in particular, an antitumor agent or an antiviral agent containing a compound which exhibits the action of enhancing IFN-xcex3 production in oral administration.
It is known that the number of eosinophils in blood or tissues increases in the case of parasite infection, hypereosinophilic syndrome (HES), eosinophilic pneumonia, eosinophilic enterogastritis, bronchial asthma, atopic dermatitis, allergic rhinitis and various other diseases in which eosinophils seem to be concerned in the pathophysiology of these diseases, and increment and activation of eosinophils are closely related to the worsening of such pathophysiology. In view of such situation, it is estimated that a compound which inhibits increment of eosinophils will be markedly useful in treating diseases in which eosinophils are closely taking part in their pathophysiology.
A compound which is capable of enhancing the IFN-xcex3 production of splenocytes of a mammal including human by oral administration is also estimated to be useful as an antitumor agent or an antiviral agent.
Taking the aforementioned situation into consideration, the inventors of the present invention have conducted studies for many years on the screening of compounds capable of strongly inhibiting increment of eosinophils. As a result of such efforts, it has been found that a compound having a specific benzimidazole skeleton can inhibit increment of eosinophils strongly and has high safety with less side effects. The present invention has been completed on the bases of such finding.
The inventors of the present invention have also conducted an intensive study on the compounds having a specific benzimidazole skeleton and found that such compounds have the action of promoting the IFN-xcex3 production of splenocytes of a mammal including human by oral administration. The present invention has also been completed on the bases of such finding.
A first aspect of the present invention is a compound represented by the following formula (I) 
(wherein R1 represents hydrogen atom or a straight- or branched-chain alkyl group having 1 to 4 carbon atoms, R2 represents cyano group, hydroxymethyl group, 2-(2-imidazolyl)ethenyl group, a phenyl group substituted by one or two xe2x80x94COOR3 groups, or a group xe2x80x94COOR3 or xe2x80x94CONR4R5, R3 represents hydrogen atom or a straight- or branched-chain alkyl group having 1 to 4 carbon atoms, each of R4 and R5 represents hydrogen atom, an alkyl group having 1 or 2 carbon atoms or a group xe2x80x94CH2COOR6 or xe2x80x94CH(CH2Ph)COOR6, wherein R4 and R5 may be the same or different from each other but, when one of R4 and R5 is a group xe2x80x94CH2COOR6 or xe2x80x94CH(CH2Ph)COOR6, the other one is hydrogen atom, A represents any one of groups selected from the class consisting of xe2x80x94COxe2x80x94, xe2x80x94CH(OR8)xe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94CH(NHR9)CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 and xe2x80x94CH2CH2xe2x80x94, W represents a group xe2x80x94CH2xe2x80x94 or a single bond, Q represents a phenyl group which may be substituted by one hydroxyl group, n is from 0 to 2, R6 represents a straight- or branched-chain alkyl group having 1 to 4 carbon atoms, R7 represents hydrogen atom, hydroxyl group, a halogen atom or a straight- or branched-chain alkoxyl group having 1 to 4 carbon atoms, R8 represents hydrogen atom or acetyl group and R9 represents hydrogen atom, acetyl group, phenylsulfonyl group or a benzoyl group which may be substituted by one methoxy group) or a salt thereof or a medicament which contains the same as the active ingredient.
The following shows preferred substituent groups or preferred combinations thereof in the compound of the aforementioned formula (I), though the present invention is not restricted thereby. R1 is preferably hydrogen atom. R2 is preferably a phenyl group substituted by one or two xe2x80x94COOR3 groups or a group xe2x80x94COOR3 or xe2x80x94CONR4R5, more preferably a phenyl group substituted by one or two xe2x80x94COOR3 groups or a group xe2x80x94COOR3. R3 is preferably a straight- or branched-chain alkyl group having 1 to 4 carbon atoms. A is preferably any one of xe2x80x94COxe2x80x94, xe2x80x94CH(OR8)xe2x80x94, xe2x80x94CH2Oxe2x80x94. W is preferably a group xe2x80x94CH2xe2x80x94. Q is preferably unsubstituted phenyl group. The symbol n is preferably 1 or 2, more preferably 2. R7 is preferably hydrogen atom, a halogen atom or a straight- or branched-chain alkoxyl group having 1 to 4 carbon atoms.
In a preferred combination of the substituent groups, R1 is hydrogen atom, W is a group xe2x80x94CH2xe2x80x94, A is any one of groups selected from the class consisting of xe2x80x94COxe2x80x94, xe2x80x94CH(OR8)xe2x80x94 and xe2x80x94CH2Oxe2x80x94 and R2 is xe2x80x94COOR3 or a phenyl group substituted by one or two xe2x80x94COOR3 groups, and in a particularly preferred combination, R1 is hydrogen atom, W is a group xe2x80x94CH2xe2x80x94 and the combination of A and R2 is respectively a group xe2x80x94COxe2x80x94 or xe2x80x94CH(OR8)xe2x80x94 and a group xe2x80x94COOR3, or a group xe2x80x94CH2Oxe2x80x94 and a phenyl group substituted by one or two xe2x80x94COOR3 groups.
In a more preferable embodiment, the compound is a compound represented by the following formula (I)-v 
(wherein R represents hydrogen atom or a lower alkyl groups) or a pharmaceutically acceptable salt thereof.
A second aspect of the present invention is an optically active compound represented by the following formula (I)-w 
(wherein R represents hydrogen atom or a lower alkyl group, and * is an asymmetric carbon atom) or a pharmaceutically acceptable salt thereof. In a more preferable embodiment, the compound is a (xe2x88x92) isomer.
A third aspect of the present invention is a process for producing the compound of formula (I) of claim 1 or a salt thereof, which comprises treating a compound represented by the following formula (III) 
(wherein Y represents acetyl group, xe2x80x94COOR3, a halogen atom, formyl group, chloroformyl group or bromoformyl group, R1 and R3 independently represents hydrogen atom or a straight- or branched-chain alkyl group having 1 to 4 carbon atoms, R7 represents hydrogen atom, hydroxyl group, a halogen atom or a straight- or branched-chain alkoxyl group having 1 to 4 carbon atoms, Q represents a phenyl group which may be substituted by one hydroxyl group and n is from 0 to 2) or a salt thereof in accordance with any one of the steps selected from the group consisting of the following steps (a) to (k):
(a) the compound is allowed to react with carbon dioxide in the presence of an inorganic base or an organic base or with a carbamato complex in an inert solvent, thereby obtaining corresponding carboxylic acid derivatives,
(b) the compound is allowed to react with halogeno-formic acid ester, dialkyl carbonate, phosphonoformic acid ester or oxalic acid ester in the presence of a base,
(c) the compound is allowed to react with malonic acid ester in the presence of a base, and then subjected to hydrolysis and subsequent decarboxylation,
(d) an acetic acid or an acetic acid ester is prepared into a metal reagent using a metalating agent, and then the compound is allowed to react with the reagent,
(e) a halogeno-acetic acid derivative is prepared into Reformatsky reagent, and then the compound is allowed to react with the reagent,
(f) the compound is allowed to react with Meldrum""s acid in the presence of a base to convert it into acyl Meldrum""s acid which is then subjected to solvolysis and decarboxylation using an alcohol, (
g) the compound is allowed to react with a malonic acid ester,
(h) using a transition metal complex, the compound is allowed to undergo cross-coupling reaction with an acetylene compound, and then hydration is carried out,
(i) the compound is subjected to halogen-metal exchange reaction using an organic lithium reagent, allowed to react with ethylmalonyl chloride and then subjected to hydrolysis and decarboxylation,
(j) the compound is reduced using a metal hydride, allowed to react with substituted benzyl halides in the presence of a base,
(k) the compound is allowed to react with hydrogen cyanide or trimethylsilyl cyanide in the presence of a Lewis acid, and then hydrolyzed.
A fourth aspect of the present invention is a medicament, particularly a pharmaceutical composition, which contains at least one of the compounds represented by the formula (I) or a salt thereof as the active ingredient.
A fifth aspect of the present invention is agents for preventing and/or treating diseases exhibiting eosinophilia, which contains a compound represented by the formula (I) or a salt thereof as the active ingredient.
A sixth aspect of the present invention is agents for preventing and/or treating bronchial asthma, which contains a compound represented by the formula (I) or a salt thereof as the active ingredient.
A seventh aspect of the present invention is agents for preventing and/or treating allergic diseases, which contains a compound represented by the formula (I) or a salt thereof as the active ingredient.
In the specification of this invention, the term xe2x80x9cdiseases exhibiting eosinophiliaxe2x80x9d means diseases in which eosinophils seem to be concerned in the pathophysiology of these diseases such as parasite infection, hypereosinophilic syndrome (HES), eosinophilic pneumonia (PIE syndrome), eosinophilic enterogastritis, bronchial asthma, atopic dermatitis, allergic rhinitis, urticaria, hypersensitivity pneumonitis, pulmonary aspergillosis, eosinophilic leukemia and the like.
An eighth aspect of the present invention is an enhancer for interferon xcex3 production containing at least one of the compounds represented by the formula (I) or a pharmaceutically acceptable salt thereof, and in particular, such an enhancer for oral administration.
A ninth aspect of the present invention is an enhancer for interferon y production of an immunocompetent cell containing at least one of the compounds represented by the formula (I) or a pharmaceutically acceptable salt thereof, and in particular, such an enhancer for oral administration.
A tenth aspect of the present invention is an antitumor agent containing at least one of the compounds represented by the formula (I) or a pharmaceutically acceptable salt thereof, and in particular, such an antitumor agent for oral administration.
An eleventh aspect of the present invention is an antiviral agent containing at least one of the compounds represented by the formula (I) or a pharmaceutically acceptable salt thereof, and in particular, such an antiviral agent for oral administration.
According to further aspects of the present invention, there are provided a use of a substance containing at least one of the compounds represented by the formula (I) or a pharmaceutically acceptable salt thereof for a prophylactic/therapeutic agent for diseases exhibiting eosinophilia, a prophylactic/therapeutic agent for bronchial asthma, a prophylactic/therapeutic agent for allergic diseases, an enhancer for interferon xcex3 production, an antitumor agent, or an antiviral agent; a method for preventing and/or treating diseases exhibiting eosinophilia, bronchial asthma, allergic diseases, tumor, or viral diseases comprising the step of administering a substance selected from the group consisting of the compounds represented by the formula (I), an optically active compound thereof, and a pharmaceutically acceptable salt thereof to a mammal including human.